PROJECT SUMMARY Cancer cells are able to adapt to grow uncontrollably and invasively in environments with limited availability of nutrients ? most notably, glucose and oxygen. Indeed, the aggressive migration and invasion of high- grade gliomas, including glioblastoma multiforme (GBM), into healthy brain tissue are major factors contributing to the therapy resistance and poor prognosis of this malignancy. While many cancer cells preferentially utilize glycolysis to support growth, GBM cells have been shown to rely on both glycolysis and mitochondrial metabolism for glucose energy utilization. Mitochondrial dynamics, or the balance between mitochondrial fission and fusion, is a central mechanism for bioenergetic adaptations to cellular stresses such as nutrient deprvation. Therefore, targeting de-regulated mitochondrial function is a highly attractive therapeutic strategy for GBM. Recent findings have established key roles for NF-?B-inducing kinase (NIK/MAP3K14) in regulating mitochondrial dynamics and subcellular trafficking to promote the invasiveness and pathogenesis of GBM cells. Moreover, preliminary data demonstrate that mitochondrial NIK enhances the resistance of GBM cells to nutrient/glucose starvation through regulation of mitochondrial metabolism. Moreover, the mitochondrial actions of NIK are independent of its regulation of NF-?B activity. However, the molecular mechanisms by which NIK coordinates regulation of mitochondrial function and metabolic reprogramming in GBM cells are currently not known. This proposal tests the hypothesis that NIK is induced by, and is an important regulator of, mitochondrial dynamics, cancer cell metabolism and infiltrative growth in response to nutrient deprivation. The goals of the proposal are to functionally define NIK-dependent regulatory networks and metabolic pathways that regulate cancer cell mitochondrial functions and test the whether NIK inhibition will sensitize GBM cells to nutrient starvation and attenuate tumor cell survival and pathogenesis. This proposal is anticipated to have an important positive impact because understanding the molecular basis of NIK mitochondrial functions is likely to generate strong justification for the development of novel, mechanism-based therapies for GBM that target mitochondrial dysfunction, invasion, and de-regulated metabolism through NIK inhibition with the ultimate goal of improving patient survival. !